The present invention relates to heterocyclic-cyclic amine derivatives of the formula I below, and pharmaceutically acceptable salts of such compounds. The compounds of formula I are cholinesterase inhibitors and are useful in enhancing memory in patients suffering from dementia and Alzheimer""s disease.
Alzheimer""s disease is associated with degeneration of a cholinergic neurons in the basal forebrain that play a fundamental role in cognitive functions, including memory. Becker et al., Drug Development Research, 12, 163-195 (1988). As a result of such degeneration, patients suffering from the disease exhibit a marked reduction in acetylcholine synthesis, choline acetyltransferase activity, acetylcholinesterase activity and choline uptake.
It is known that acetylcholinesterase inhibitors are effective in enhancing cholinergic activity and useful in improving the memory of Alzheimer""s patients. By inhibiting acetylcholinesterase enzyme, these compounds increase the level of the neurotransmitter acetylcholine, in the brain and thus enhance memory. Becker et al., supra, report that behavioral changes following cholinesterase inhibition appear to coincide with predicted peak levels of acetylcholine in the brain. They also discuss the efficacy of the three known acetylcholinesterase inhibitors physostigmine, metrifonate, and tetrahydroaminoacridine.
European Patent Application EP A 0 229 391 relates to piperidine derivatives of the formula: R1xe2x80x94Xxe2x80x94Axe2x80x94R2. European Patent Application EP A 296 560 relates to a cyclic amine compound of the formula 
All documents cited herein, including the foregoing, are incorporated herein in their entireties.
The present invention relates to compounds of the formula 
wherein R1 and R2 are independently selected from hydrogen, (C1-C6)alkoxy, benzyloxy, phenoxy, hydroxy, phenyl, benzyl, halo, nitro, cyano, COR5, xe2x80x94COOR5, xe2x80x94CONHR5, xe2x80x94NR5R6, xe2x80x94NR5COR6, xe2x80x94OCONR5R6, xe2x80x94NHCOOR5, (C1-C6)alkyl optionally substituted with from 1 to 3 fluorine atoms; SOpCH2-phenyl or SOp(C1-C6)alkyl, wherein p is 0, 1 or 2; pyridylmethyloxy or thienylmethyloxy; 2-oxazolyl, 2-thiazolyl and benzenesulfonamide; wherein the phenyl moieties of said phenoxy, benzyloxy, phenyl, benzyl and benzenesulfonamide groups, the pyridyl and thienyl moieties of said pyridylmethyloxy or thienylmethyloxy and the oxazolyl and thiazolyl moieties of said 2-oxaxolyl and 2-thiazolyl may optionally be substituted with 1 or 2 substituents independently selected from halo, (C1-C4)alkyl, trifluoromethyl, (C1-C4)alkoxy, cyano, nitro and hydroxy.
or R1 and R2, when attached to adjacent carbon atoms and when X is oxygen, sulfur or NR4 wherein R4 is hydrogen or (C1-C4 alkyl) may form, together with the carbon atoms to which they are attached, a group of the formula 
xe2x80x83wherein J is oxygen, sulfur or NR4, xe2x80x9caxe2x80x9d is 1 or 2, R3 is hydrogen or (C1-C6)alkyl and Q is oxygen, sulfur, NH, CHCH3, C(CH3)2, xe2x80x94CHxe2x95x90CHxe2x80x94, or (CH2)l wherein l is an integer from 1 to 3;
X is oxygen, sulfur, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, or NR4 wherein R4is hydrogen or (C1-C4)alkyl;
Y is xe2x80x94(CH2)mxe2x80x94, xe2x80x94CHxe2x95x90CH(CH2)nxe2x80x94, xe2x80x94NR4(CH2)mxe2x80x94, or xe2x80x94O(CH2)mxe2x80x94 wherein R4 is defined as above, n is an integer from 0 to 3 and m is an integer from 1 to 3;
R5 and R6 are each independently selected from hydrogen, (C1-C6)alkyl, phenyl or benzyl, wherein the phenyl moieties of said phenyl and benzyl may optionally be substituted with 1 or 2 substituents independently selected from fluoro, chloro, bromo, iodo, (C1-C4)alkyl, trifluoromethyl, (C1-C4)alkoxy, cyano, nitro and hydroxy, or NR5R6 together form a 4 to 8 membered ring wherein one atom of the ring is nitrogen and the others are carbon, oxygen or nitrogen (e.g. pyrrolidinyl, piperidinyl, morpholino, piperazinyl or N-methylpiperazinyl), or NR5COR6 together form a 4 to 8 membered cyclic lactam ring;
M is xe2x80x94CHxe2x80x94 or nitrogen;
L is phenyl, phenyl-(C1-C6)alkyl, cinnamyl or pyridylmethyl, wherein the phenyl moieties of said phenyl and phenyl-(C1-C6)alkyl may optionally be substituted with 1 to 3 substituents independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C6)alkylcarbonyl, xe2x80x94OCONR5R6, xe2x80x94NHCOOR5 or halo; or L is a group of the formula 
xe2x80x83wherein b is an integer from 1 to 4, R13 and R14 are independently selected from hydrogen, (C1-C4)alkyl, halo and phenyl, E and F are independently selected from xe2x80x94CHxe2x80x94 and nitrogen, and G is oxygen, sulfur or NR4 wherein R4 is defined as above, with the proviso that when E and F are both nitrogen, one of R13 and R14 is absent; and
R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl and (C1-C6)alkoxy, with the proviso that said (C1-C6)alkoxy is not attached to a carbon that is adjacent to a nitrogen.
This invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. Examples of such pharmaceutically acceptable acid addition salts are the salts of hydrochloric acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, succinic acid, salicylic acid, oxalic acid, hydrobromic acid, phosphoric acid, methanesulfonic acid, tartaric acid, di-p-toluoyl tartaric acid, and mandelic acid.
This invention also relates to a pharmaceutical composition for inhibiting cholinesterase comprising a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier.
This invention also relates to a method for inhibiting cholinesterase in a mammal comprising administering to a mammal an amount of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof effective in inhibiting cholinesterase.
This invention also relates to a method for enhancing memory or treating or preventing Alzheimer""s disease in a mammal comprising administering to a mammal an amount of a compound of the formula I or a pharmaceutically acceptable acid addition salt thereof effective in enhancing memory or treating or preventing Alzheimer""s disease.
This invention also relates to compounds of the formula 
wherein W is a leaving group; j is an integer from 0 to 2; R10 is a nitrogen protecting group; and R7 and R8 are independently selected from hydrogen, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl and (C1-C6)alkoxy, with the proviso that said (C1-C6)alkoxy is not attached to a carbon that is adjacent to a carbon that is adjacent to a nitrogen. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
This invention also relates to compounds of the formula 
wherein
R1, R2,
R7, R8,
X, Y and M are as defined above and R11 is hydrogen or a nitrogen protecting group. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
This invention also relates to compounds of the formula: 
wherein R1, R2, R7, R8 and L are as defined above and Yxe2x80x2 is xe2x80x94CHxe2x95x90CHxe2x80x94(CH2)nxe2x80x94 or xe2x80x94(CH2)mxe2x80x94. These compounds are useful as intermediates in the synthesis of compounds of the formula I.
The term xe2x80x9cmammalxe2x80x9d, as used herein, includes humans.
The term xe2x80x9chaloxe2x80x9d, as used herein, includes chloro, bromo, iodo or fluoro.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched, or cyclic moieties or combinations thereof.
The term xe2x80x9c(C1-C4)alkylcarbonylxe2x80x9d, as used herein, refers to a substituent of the formula 
wherein R15 is alkyl.
The term xe2x80x9c(C1-C4)alkoxycarbonylxe2x80x9d, as used herein, refers to a substituent of the formula V above, wherein R15 is (C1-C4)alkoxy.
The term xe2x80x9c(C1-C6)alkoxycarbonylxe2x80x9d, as used herein, refers to a substituent of the formula V above, wherein R15 is (C1-C6)alkoxy.
The term xe2x80x9c(C1-C6)alkylcarbonylxe2x80x9d, as used herein, refers to a substituent of the formula V above, wherein R15 is (C1-C6)alkyl.
Preferred compounds of this invention are compounds of the formula I wherein X is oxygen or sulfur, Y is xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, M is xe2x80x94CHxe2x80x94 and L is benzyl, R1 and R2 are (C1-C6)alkyl, (C1-C6)alkoxy, NR5R6, or NR5COR6, R3 is hydrogen or (C1-C6)alkyl, J is oxygen or sulfur and Q is CH(CH3), CH(CH3)2, xe2x80x94CHxe2x95x90CH or (CH2)l and the pharmaceutically acceptable salts of such compounds.
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5-Methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5,6-Dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
7-Methoxy-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Acetamido-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Amino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Benzamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-1,2-benzisoxazole;
6-Benzenesulfonamide-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-(4-Morpholinyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
1-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-isoquinoline;
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisothiazole;
4-[2-[-(Phenylmethyl)-4-piperidnyl]ethyl]-1,3-quinazoline;
6-Hydroxy-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazole;
6-Bromo-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazole;
6-Cyano-3-[2-[1-(phenylmethyl)-4-piperidyl]ethyl]-1,2-benzisoxazole;
6-Carboxamide-3-[2-[1-(phenylmethyl)-4-piperidyl]-ethyl]-1,2-benzisoxazole;
3-[(1-Phenylmethyl-4-piperidyl)methoxy]-1,2-benzisoxazole;
3-[(1-Phenylmethyl-4-piperidyl)methylamino]-1,2-benzisoxazole;
3-[2-(1-Phenylmethyl)-4-piperidyl)ethylamino]-1,2-benzisoxazole;
3-[3-[1-(Phenylmethyl)-4-piperidyl]propyl]-1,2-benzisoxazole;
trans-3-[2-[1-(Phenylmethyl)-4-piperidyl]ethenyl]-1,2-benzisoxazole;
3-[2-[1-(Phenylmethyl)-4-piperazinyl]ethyl]-1,2-benzisoxazole;
5,7-Dihydro-7-methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-7-ethyl-3-[2[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(2-chloro-5-thiophenemethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(2-methyl-4-thiazolemethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(3-Bromophenylmethyl)-4-piperidinyl]-5,7-dihydro-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(4-Bromophenylmethyl)-4-piperidinyl]ethyl]-5,7-dihydro-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[3-[1-(phenylmethyl)-4-piperidinyl]propyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-5,6,8-trihydro-7H-isoxazolo[4,5-g]quinolin-7-one;
6,8-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-7H-pyrrolo[5,4-g]-1,2-benzisoxazol-7-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[5,4-f]-1,2-benzisoxazol-6-one;
3-[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-1H-indazole;
and the pharmaceutically acceptable salts of such compounds.
Examples of other compounds of the formula I are:
6-Phenylamino-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-(2-Thiazolyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-(2-Oxazolyl)-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Pyrrolidinyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
6-Piperidinyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1,2-benzisoxazole;
5,7-Dihydro-5,5-dimethyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]-ethyl]-7-n-propyl-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-7-i-propyl-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
5,7-Dihydro-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo[4,5-f]-1,2-benzisoxazol-6-one;
3[2-[1-(Phenylmethyl)-4-piperidinyl]ethyl]-6-phenylmethylsulfone-1,2-benzisoxazole;
1-Methyl-3-[2-[1-(phenylmethyl)-4-piperidinyl]ethyl]-1H-indazole; and
3-[1-Phenylmethyl-4-piperidinyl)methyl]-1,2-benzisoxazole.
The compounds of formula I may have optical centers and may therefore occur in different isomeric forms. The invention includes all stereoisomers of such compounds of formula I, including mixtures thereof.
The preparation of compounds having the formula I and certain of the starting materials used in their synthesis is illustrated in the following reaction schemes. Except where otherwise stated, in the reaction schemes and discussion that follow, R1, R2, R3, R4, R5, R6, R7, R8, R13, R14, E, G, X, Y, M, L, a, b, l, m, n, p, and structures I, A, B, and K are defined as above.
All articles, books, patents and patent applications cited in the following discussion are incorporated herein by reference. 
The preparation of compounds of the formula I wherein Y is xe2x80x94(CH2)m and M is xe2x80x94CHxe2x80x94 is illustrated in scheme 1. These compounds are designated in scheme 1 and hereinafter referred to as compounds of the formula I-A (those wherein L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K) and compounds of the formula I-B (those wherein L is phenyl or cinnamyl).
Referring to scheme 1, compounds of the formula I-A may be prepared by deprotonating a compound of the formula II with a base in the presence of, or followed by the addition of an alkylating agent of the formula III wherein R10 is a nitrogen protecting group and W is a leaving group. When R10 is a nitrogen protecting group, this reaction produces an intermediate of the formula IV. This intermediate is then deprotected to yield a secondary piperidine of the formula VI as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K.
Examples of suitable leaving groups (W) are mesylate, tosylate, chloride, iodide and bromide. Examples of suitable nitrogen protecting groups (R10) are amides such as N-formyl and N-acetyl and carbamates such as t-butoxycarbamate (BOC). The preferred nitrogen protecting group is BOC. Appropriate bases for use in the preparation of compounds of the formula IV include strong bases such as lithium diisopropylamide (LDA), n-butyllithium, s-butyllithium, and lithium (or sodium or potassium) hexamethyldisilazide (LiHMDS, NaHMDS, or KHMDS). LDA and s-butyllithium are preferred.
The reaction of a compound of formula II with a compound of formula III is generally carried out in a polar, aprotic solvent such as diethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran (THF). Temperatures may range from about xe2x88x9278xc2x0 C. to about 30xc2x0 C. This reaction is preferably conducted in THF at about xe2x88x9278xc2x0 C.
Usually, compounds of the formula II are deprotonated in the presence of a compound of formula III. However, in cases where the compound of formula II has more than one acidic proton, it is preferable to carry out the deprotonation step first followed by the immediate and rapid addition of the alkylating agent of formula II.
The protecting group (R10) can be removed from compounds of the formula IV to form the corresponding compounds of formula VI by methods known to those skilled in the art. For example, when R10 is BOC or another carbamate, it can be removed with an acid such as hydrogen bromide (gas or aqueous), hydrogen chloride (gas or aqueous) or trifluoroacetic acid. In the case of trifluoroacetic acid, a t-butyl cation scavenger such as thioanisole may be added. When an acid is used as the deprotecting agent, an acid addition salt of the compound of formula VI is produced rather than the free base of such compound. Appropriate solvents include non-polar solvents such as methylene chloride, as well as polar solvents such as diethyl ether, ethyl acetate, dioxane, alcohols (e.g. methanol or ethanol) and water. Temperatures may range from about xe2x88x9220xc2x0 C. to about the reflux temperature of the solvent. It is preferable to use trifluoroacetic acid in methylene chloride with or without thioanisole at about 0xc2x0 C.
Alternatively, when R10 is BOC, it can be removed with a trialkylsilyltrifluoromethanesulfonate derivative such as trimethylsilyl-, triethylsilyl-, or t-butyldimethylsilyltrifluoromethanesulfonate in the presence of an aromatic or tertiary amine base such as 2,6-lutidine or triethylamine. Appropriate solvents for this reaction include norpolar solvents such as methylene chloride and polar aprotic solvents such as THF, diethyl ether or DMF. Temperatures may range from about xe2x88x9220xc2x0 C. to room temperature. It is preferable to use trimethylsilyltrifluoromethane-sulfonate and 2,6-lutidine in methylene chloride at a temperature from about 0xc2x0 C. to about room temperature.
The intermediate secondary piperidine of the formula VI, obtained as the free base or salt as described above, is reacted with 2-10 equivalents of a base and then with an alkylating agent of the formula WL, wherein W is defined as above and L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K. Suitable bases include tertiary amines such as triethylamine and diisopropylethyl-amine, aromatic amines such as pyridine and dimethylaminopyridine, and metal carbonates such as sodium bicarbonate or sodium or potassium or cesium carbonate. When W is chloride, catalytic iodide (potassium iodide or tetra-n-butylammonium iodide) may be added. Appropriate solvents include non-polar solvents such as methylene chloride and polar solvents such as dimethylformamide, THF, acetontrile, acetone, dioxane, and alcohols such as methanol or ethanol. It is preferable to carry out the alkylation in the presence of triethylamine in methylene chloride at room temperature or in the presence of sodium carbonate in dimethylformamide at room temperature.
Alternatively, the intermediate secondary piperidine of formula VI, when obtained as a salt after removal of the protecting group, can be deprotonated to the free amine by dissolving or suspending it in an appropriate solvent (e.g., methylene chloride or ethyl acetate), mixing it with aqueous sodium bicarbonate or aqueous sodium or potassium hydroxide and recovering the free amine from the organic layer by conventional extraction techniques. The free amine can then be subjected to alkylation with the appropriate alkylating agent of the formula WL under the conditions described above using 1-2 equivalents of an appropriate base.
The starting materials of formula II can be prepared according to methods known in the art. When X is oxygen, the starting 3-methyl-1,2-benzisoxazoles can be prepared by procedures similar to those described by Wunsch et al., Adv. Heterocycl. Chem., 1967, 8, 277; Smalley, R. K., Adv. Heterocycl. Chem. 1981, 29, 2; and Thakar et al., Indian J. Chem. 1977, 15B, 1058. The appropriate o-hydroxy acetophenones are converted to the corresponding oximes by reaction with hydroxylamine hydrochloride in the presence of an appropriate base such as potassium or sodium hydroxide, sodium acetate or pyridine, preferably aqueous potassium hydroxide or aqueous sodium acetate, in a polar solvent such as methanol, ethanol, or water, preferably ethanol, at a temperature from about room temperature to about 120xc2x0 C. The oxime is then converted to the corresponding oxime acetate by acetylation with an appropriate acylating agent such as acetic anhydride. Temperatures for this reaction may range from about room temperature to the reflux temperature of the solvent. Temperatures between 80xc2x0 C. and 130xc2x0 C. are preferred.
Ring closure to form the benzisoxazole ring may be carried out by heating the neat oxime acetate at a temperature from about 125xc2x0 C. to about 200xc2x0 C. under atmospheric pressure or reduced pressure (e.g., from about 0.01 mm Hg (1.33xc3x9710xe2x88x925 bars) to about 760 mm Hg (1.01 bars)). Ring closure is preferably accomplished by heating the oxime acetate at reflux in an appropriate base such as pyridine, or by heating the oxime acetate at a temperature of about 130xc2x0 C. in a polar solvent such as DMF or DMSO (dimethylsulfoxide) in the presence of several equivalents of an appropriate base such as pyridine or 2,6-lutidine.
Alternatively, ring closure can be carried out directly from the oxime by reaction with an acyl or sulfonyl chloride such as oxalyl or thionyl chloride in the presence of an aromatic amine such as pyridine (See Kalkote et al., Aust. J. Chem. 1977, 30, 1847). Suitable solvents include polar solvents such as diethyl ether or THF. Temperatures can range from about 0xc2x0 C. to about room temperature. Another method of closure involves treatment of the oxime with one or less equivalents of a base such as potassium hydroxide in a polar solvent such as methanol at temperatures ranging from about room temperature to about 100xc2x0 C. (Crabbe et al., J. Chem. Soc. Perkin Trans. I, 1973, 2220).
When X is sulfur, the starting 3-methyl-1,2-benzisothiazoles can be prepared from o-methylthio acetophenones following procedures similar to those described above for the benzisoxazoles (See McKinnon et al., Can. J. Chem., 1988, 66, 1405 and references cited therein) The o-methylthio acetophenones are converted into the corresponding oximes and ring closure is carried out directly by reaction with an appropriate acylating agent such as acetic anhydride in a base such as pyridine. The reaction temperature may range from about room temperature to about 130xc2x0 C., and is preferably about 120xc2x0 C.
When X is NR4 wherein R4 is hydrogen the starting 3-methyl-1H-indazoles can be prepared according to methods described by Behr et al., xe2x80x9cPyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings,xe2x80x9d Heterocyclic Compounds, R. H. Wiley, Ed., 1967, 289; Bartsch et al., J. Heterocycl. Chem., 1984, 21, 1063; Hannig et al., Pharmazie 1976, 31, 534; Barton et al., J. Chem. Soc. Chem. Comm., 1982, 450; Ruechardt et al., Liebigs Ann. Chem., 1980, 908; and Rees et al., J. Chem. Soc. D, 1971, 827. N-Alkylation of 3-methyl-1H-indazoles (X is NR4 wherein R4 is (C1-C4)alkyl) can be carried out as described by Behr et al., xe2x80x9cPyrazoles, Pyrazolines, Pyrazolidines, Indazoles, and Condensed Rings,xe2x80x9d Heterocyclic Compounds, R. H. Wiley, Ed., 1967, 309; Palmer et al., J. Chem. Soc., Perkin Trans. II, 1975, 1695; and Claramunt et al., Heterocycles 1985, 23, 2895.
When X is xe2x80x94CHxe2x95x90CHxe2x80x94, the starting 1-methylisoquinolines can be prepared according to the Bischler-Napieralksi or Pictet-Spengler methods (See Organic Reactions, Vol. VI, chapters 2 and 3, pp. 74-190, John Wiley and Sons, New York, 1951).
When X is xe2x80x94Nxe2x95x90CHxe2x80x94, the starting 4-methylquinazolines can be prepared according to methods described by Byford et al., Indian J. Chem., 1988, 27B, 396; Higashino, T., Chem. Pharm. Bull., 1962, 10, 1043; and Uff et al., J. Chem. Soc., Perkin Trans. I, 1986, 2295.
When X is xe2x80x94CHxe2x95x90Nxe2x80x94 the starting 1-methylphthalazines can be prepared according to methods described by Kant et al., J. Heterocycl. Chem., 1985, 22, 1065 and references cited therein; Acheson et al., J. Chem. Soc. C, 1966, 2218; and Gabriel et al., Chem. Ber. 1897, 30, 3022.
When X is xe2x80x94Nxe2x95x90Nxe2x80x94, the starting 4-methyl-1,2,3-benzotriazines can be prepared according to methods described by Adger et al., J. Chem. Soc., Perkin Trans. I, 1975, 31; Boulton et al., Ibid., 1988, 1509; and Rees et al., J. Chem. Soc. D, 1971, 828.
When one or both of R1 and R2 are NH2, the starting material of formula II may be prepared from the corresponding NHAc precursor (Ac=acetyl) by acid hydrolysis. The acid hydrolysis can be carried out with aqueous hydrochoric acid at temperatures ranging from about 50xc2x0 C. to about 120xc2x0 C. Heating to reflux (about 120xc2x0 C.) in 1N HCl is preferred. The corresponding NHBz (Bz=benzoyl) or NHSO2C6H5 compounds can be prepared from the corresponding amino derivative by reaction with the appropriate benzoyl or benzenesulfonyl chloride in the presence of a base such as triethylamine, pyridine, or dimethylaminopyridine. Suitable solvents include methylene chloride, THF, diethylether, or dimethylformamide. Temperatures may range from about xe2x88x9220xc2x0 to about 80xc2x0 C. When one or both of R1 and R2 is NHBz, it is preferable to use triethylamine/dimethylaminopyridine in methylene chloride at room temperature. When one or both of R1 and R2 is NHSO2Ph, it is preferable to use pyridine in methylene chloride at 0xc2x0 C.
Cyclic dialkylamino compounds of the formula II (i.e., those wherein one or both of R1 and R2 are NR5R6 wherein NR5R6 together form a ring) can also be prepared from the corresponding amino derivative by alkylation with the appropriate bis-halide reagent of the formula 
wherein each A is independently bromide or chloride and B is oxygen or (CH2)q wherein q is 0 to 2, in the presence of an appropriate base such as triethylamine or diisopropylethylamine (Hunig""s base), in an appropriate nonpolar solvent such as toluene or xylene. The alkylation is typically carried out at a temperature from about room temperature to about 150xc2x0 C. It is preferably conducted in the presence of Hunig""s base in toluene at about 120xc2x0 C. (reflux). (See Verboom et al., J. Org. Chem. 1984, 49, 269).
Alternatively, these cyclic dialkylamino derivatives may be prepared by nucleophillic displacement of an aromatic fluoride with the appropriate cyclic amine. Suitable solvents for this reaction include polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, pyridine and hexamethylphosphoramide. Acetonitrile and pyridine are preferred. The reaction may be run in the presence of a base such as a tertiary or aromatic amines (e.g., triethylamine, diisopropylethylamine, pyridine or dimethylaminopyridine), preferably pyridine or triethylamine. The reaction temperature may range from about room temperature to about 160xc2x0 C., and is preferably from about 80xc2x0 C. to about 160xc2x0 C.
When R1 and R2, together with the carbons to which they are attached, form a group of the formula 
and X is oxygen or sulfur, the starting material of formula II may be prepared by the following procedure which is illustrated only for cases wherein R1 and R2 form a group of formula A. 
First, a compound of the formula VIII wherein Xxe2x80x2 is hydroxy, thiol or methyl sulfide is prepared by Friedel-Crafts acylation of the corresponding compound of the formula VII, wherein Xxe2x80x3 is methoxy or methyl sulfide with an acylating agent such as acetyl chloride or acetic anhydride, preferably acetyl chloride, in the presence of a Lewis acid such as aluminum chloride, titanium tetrachloride or boron triflouride etherate, preferably aluminum chloride. Appropriate solvents include carbon disulfide, 1,2-dichloroethane and nitrobenzene. Carbon disulfide and 1,2-dichloroethane are preferred. Generally, this reaction is conducted at a temperature from about room temperature to about 200xc2x0 C., preferably from about 50xc2x0 C. to about 100xc2x0 C.
Alternatively, a compound of formula VIII wherein Xxe2x80x2 is hydroxy, may also be obtained by Fries rearrangement of the corresponding compound of the formula VII wherein Xxe2x80x3 is acetyloxy. A mixture of VII and a Lewis acid such as aluminum chloride, boron trifluoride etherate or titanium tetrachloride is heated at temperatures from about 80xc2x0 C. to 200xc2x0 C. either neat or in the presence of a solvent such as nitrobenzene, or 1,2-dichloroethane. The Fries rearrangment is preferably conducted neat with aluminum chloride at 170-190xc2x0 C.
The compounds of formula VIII obtained by the foregoing process may be converted to the corresponding starting materials of formula II by the procedure described above for 1,2-benzisoxazoles and 1,2-benzisothiazoles.
Referring to scheme 1, compounds of the formula III may be prepared from the corresponding compounds wherein W is hydroxy by methods known in the art. For example, compounds of the formula III wherein W is iodide can be prepared by reacting the hydroxy counterpart with iodine and triphenylphosphine in the presence of a base such as pyridine or imidazole in a non-polar solvent such as benzene or toluene at a temperature from about room temperature to about 130xc2x0 C. Preferably, the reaction is carried out in benzene in the presence of pyridine at about 90xc2x0 C. (reflux).
Compounds of the formula I-B may be prepared by deprotonating a compound of the formula II with a base in the presence of, or followed by the addition of, an alkylating agent of the formula III wherein R10 is phenyl or cinnamyl and W is defined as above. Suitable and preferred bases, solvents and conditions are similar to those described above for the preparation of compounds of the formula IV.
Scheme 2 illustrates the preparation of compounds of the formula I wherein Y is xe2x80x94CHxe2x95x90CH(CH2)nxe2x80x94 via an aldol-type condensation. These compounds are designated in scheme 2 and hereinafter referred to as compounds of the formula I-C. Referring to scheme 2, a compound of the formula IX wherein R9 is hydrogen is deprotonated with a base followed by immediate and rapid addition of an aldehyde of the formula X. Suitable bases and solvents are the same as those described above for the first reaction in scheme 1. The reaction temperature may range from about xe2x88x9278xc2x0 C. to about room temperature. The reaction is preferably carried out using lithium diisopropylamide in THF at about xe2x88x9278xc2x0 C. and allowed to warm to room temperature.
If an intermediate alcohol is formed, it can be dehydrated to the olefin under standard acidic conditions, using an acid such as dilute hydrochloric acid, p-toluenesulfonic acid or pyridinium p-toluenesulfonate, preferably p-toluenesulfonic acid, in a solvent such as benzene, toluene, THF or methylene chloride, at a temperature from about 0xc2x0 C. to about 130xc2x0 C. Preferably, the dehydration is carried out in benzene at about 80xc2x0 C. (reflux) with azeotropic removal of water. Dehydration may also be accomplished by treatment with Burgess"" reagent (Et3+NSO2xe2x88x92NCO2Me) in methylene chloride or benzene at a temperature from about room temperature to about 80xc2x0 C.
Alternatively, the intermediate alcohol may be converted into a good leaving group such as mesylate or tosylate and then eliminated with an appropriate base. The mesylate or tosylate can be prepared under standard conditions by reacting the alcohol with methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine. Appropriate solvents include methylene chloride and THF, with methylene chloride being preferred. Temperatures may range from about 0xc2x0 C. to about 60xc2x0 C., and are preferably from about 0xc2x0 C. to about room temperature. Elimination to form the olefin can then be carried out with a base such as diazabicycloundecane or diazabicyclononane in a suitable solvent such as benzene, methylene chloride, or THF, with benzene or methylene chloride being preferred, at a temperature from about 0xc2x0 C. to about 100xc2x0 C., preferably from about room temperature to about 100xc2x0 C.
Compounds of the formula I-C may also be prepared by a Wittig reaction from compounds of the formula IX wherein R9 is bromine, chlorine or iodine. According to this procedure, a compound of formula IX is converted into its phosphonium salt by treatment with triphenylphosphine in a nonpolar solvent such as benzene, toluene or xylene, preferably toluene, at a temperature from about room temperature to about 150xc2x0, preferably from about 80xc2x0 C. to about 120xc2x0 C. The phosphonium salt may then be deprotonated with a strong base such as sodium hydride, potassium t-butoxide, potassium hydride or n-butyllithium in a suitable solvent such as diethylether or THF, at a temperature from about 0xc2x0 C. to about 80xc2x0 C. The deprotonation is preferably carried out with sodium hydride in THF at about room temperature.
Scheme 2xe2x80x2 illustrates an alternative preparation of compounds of the formula I wherein X is oxygen or NR4, Y is (CH2)m or xe2x80x94CHxe2x95x90CH(CH2)n and M is carbon (i.e. xe2x80x94CHxe2x80x94). These compounds are designated in Scheme 2xe2x80x2, and hereinafter referred to as compounds of the formula I-F (those where Y is xe2x80x94CHxe2x95x90CH(CH2)nxe2x80x2 and nxe2x80x2 is an integer from 0 to 3) and I-G (those where Y is (CH2)m and nxe2x80x2 is an integer from 0 to 1). Referring to Scheme 2xe2x80x2, compounds of the formula I-F may be prepared by deprotonating a compound of the formula XV with a suitable base followed by addition of an aldehyde of formula XVI to give an intermediate of formula XVII. This intermediate is then transformed to compounds of the formula I-F by reaction with an appropriate amine.
Appropriate bases for use in the preparation of compounds of the formula XVII include lithium diisopropylamide, lithium or sodium or potassium hexamethyldisilazide, or n-butyllithium, preferably lithium diisopropylamide or lithium hexamethydisilazide. The reaction of a compound of formula XV with a compound of formula XVI is generally carried out in a polar aprotic solvent such as diethyl ether, 1,2-dimethoxyethane, or tetrahydrofuran. Temperatures may range from xe2x88x9278xc2x0 C. to 80xc2x0 C. This reaction is preferably conducted in THF at xe2x88x9278xc2x0 C. and allowed to warm to room temperature.
A compound of formula I-F is then obtained from an intermediate of formula XVII by reaction with an amine such as hydrazine or hydroxylamine in the presence of a base such as sodium or potassium hydroxide, sodium or potassium carbonate, or sodium or potassium alkoxide (methoxide or ethoxide), preferably sodium or potassium hydroxide. In some cases (when amine is hydrazine), addition of a base may not be necessary. Suitable solvents for this reaction include methanol, ethanol, i-propanol, water, or, when amine is hydrazine, hydrazine itself may be used as a solvent. Temperatures may range from 50xc2x0 C. to 120xc2x0 C. It is preferable to react XVII with hydrazine at 120xc2x0 C. (reflux), or with hydroxylamine and potassium hydroxide in EtOH/water at 100xc2x0 C. (reflux). Upon reaction with hydroxylamine, the intermediate oxime obtained may be isolated and then cylclized to compounds of the formula I-F following the suitable and preferred conditions described above for the preparation of starting materials 3-methyl-1,2-benzioxazoles.
Compounds of the formula I-G may be prepared by reducing an intermediate of formula XVII to give a compound of formula XVIII. The intermediate of formula XVII may then be reacted with an amine to give compounds of the formula I-G. An intermediate of formula XVII is reduced with hydrogen gas to an intermediate of formula XVIII in the presence of a catalyst such as palladium on carbon, platinum oxide, or rhodium on carbon, preferably platinum oxide in a polar solvents such as ethyl acetate, tetrahydrofuran, ethanol, or acetic acid, preferably EtOH. Pressure may range from atmospheric to 50 psi (3.45 bars), preferably 40-50 psi (2.76-3.45 bars) and temperature may range from room temperature to 80xc2x0 C., preferably room temperature.
A compound of formula I-G is then obtained from an intermediate of formula XVIII following the suitable and preferred conditions described above for the preparation a compound of formula I-F from an intermediate of formula XVII.
Scheme 3 illustrates the preparation of compounds of the formula I wherein Y is xe2x80x94O(CH2)mxe2x80x94 or xe2x80x94NR4(CH2)m. These compounds are designated in scheme 3 and hereinafter referred to as compounds of the formula I-D. Referring to scheme 3, compounds of the formula I-D may be prepared by reacting a compound of the formula XI wherein R12 is chloro or bromo, with a nucleophile of the formula XII, wherein Z is xe2x80x94NHR4 or xe2x80x94OH. When Y is NR4(CH2)m (i.e., Z is xe2x80x94NHR4), the amine of formula XII is generally reacted with the appropriate compound of formula XI either neat or in a polar solvent such as dimethylformamide (DMF), dimethylsulfoxide (DMSO), THF or pyridine. DMSO and DMF are preferred solvents. An acid acceptor such as diazabicycloundecane, pyridine, lutidine, triethylamine or metal carbonates such as potassium or sodium or cesium carbonate may be added. Metal carbonates such as potassium carbonate are preferred. The reaction temperature may range from about room temperature to about 160xc2x0 C. and is preferably from about 100xc2x0 C. to about 160xc2x0 C.
When Y is O(CH2)m (i.e., Z is xe2x80x94OH), the alkoxide anion is formed and this species is reacted with the compound of formula XI. According to this procedure, the alcohol (XII) is deprotonated with a suitable base, after which the appropriate compound of formula XI is added and the mixture is heated. Examples of suitable bases are sodium, sodium hydride and potassium hydride with sodium hydride being preferred. Suitable solvents include THF, DMF and DMSO, with THF and DMF being preferred. This reaction is generally conducted at a temperature from about 40xc2x0 C. to about 160xc2x0 C. Temperatures between about 60xc2x0 C. and about 160xc2x0 C. are preferred.
Alternatively, compounds of the formula I-D may be prepared by reacting a compound of formula XI with a nucleophile of the formula XIX wherein Z and R10 are defined as above. This reaction produces an intermediate of formula XX which is then deprotected to yield a secondary piperidine of formula XXI as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethyl, or a group of the formula K.
Suitable and preferred bases, solvents, and conditions for the reaction of a compound of formula XI with a nucleophile of the formula XIX are similar to those described for the reaction of a compound of the formula XI with a nucleophile of the formula XII for the preparation of compounds of the formula I-D. Suitable and preferred bases, solvents, and conditions for the transformations of compounds of the formulas XX and XXI to prepare compounds of the formula I-D are similar to those described in scheme 1 for compounds of the formulas IV and VI to prepare compounds of the formula I-A.
Scheme 4 illustrates the preparation of compounds of the formula I wherein Y is xe2x80x94(CH2)mxe2x80x94 and M is nitrogen. These compounds are designated in scheme 4 and hereinafter referred to as compounds of the formula I-E. Referring to scheme 4, a compound of the formula XIII wherein R12 is chloro, bromo or iodo is reacted with a compound of the formula XIV. This reaction may be carried out in the presence of an acid acceptor such as pyridine, 2,6-lutidine or a metal carbonate (e.g., sodium bicarbonate or sodium or potassium carbonate). When R12 is chloro or bromo, a catalytic amount of a displacement promoter may be added. Examples of suitable displacement promoters are sodium iodide, potassium iodide or tetra-n-butylammonium iodide. Generally, this reaction is conducted in a nonpolar solvent such as toluene or xylene, or in a polar solvent such as THF, DMF or DMSO, preferably xylene or DMF, at a temperature from about room temperature to about 160xc2x0 C., preferably from about 90xc2x0 C. to about 160xc2x0 C.
Scheme 5 illustrates the preparation of compounds of the formula I wherein X is xe2x80x94Nxe2x95x90CHxe2x80x94 and M is carbon (i.e. xe2x80x94CH). These compounds are designated in scheme 5 and hereinafter referred to as compounds of the formula I-H. Referring to scheme 5, a compound of the formula IIxe2x80x2 may be deprotonated with one equivalent of a base followed by addition of a silylating agent (trimethylsilyl chloride). Sequential deprotonation with a second equivalent of the same base followed by addition of an alkylating agent of the formula III and appropriate work-up produces an intermediate of the formula IVxe2x80x2. This intermediate is then deprotected as described in scheme I to yield a secondary piperidine of formula VIxe2x80x2 as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethyl, or a group of the formula K.
Suitable bases, solvents, and temperatures for deprotonation of a compound of the formula IIxe2x80x2 are the same as those described above for the first reaction in scheme I, preferably LDA in THF at 0xc2x0 to room temperature. After addition of the first equivalent of base, a silylating agent such as trimethylsilyl or triethylsilyl chloride is added, preferably trimethylsilyl chloride. A second equivalent of the same base is then added followed by an alkylating agent of the formula III. The trimethylsilyl group is then removed under acidic conditions by stirring the crude reaction mixture with dilute hydrochloric acid for 30-60 min at room temperature. Then, the crude reaction mixture is made basic with aqueous sodium carbonate, or aqueous sodium or potasium hydroxide, preferably aqueous sodium hydroxide, and the intermediate of formula IVxe2x80x2 is extracted with an organic solvent by conventional extraction techniques. Suitable and preferred conditions for the transformation of intermediates of the formula IVxe2x80x2 to compounds of the formula I-H are the same described in scheme I for the preparation of compounds of the formula I-A.
Scheme 6 illustrates the preparation of compounds of the formula I wherein Y is (CH2)m. M is carbon (i.e. xe2x80x94CHxe2x80x94), J is sulfur and Q is CHCH3, C(CH3)2, xe2x80x94CHxe2x95x90CH, or (CH2)l. These compounds are designated in scheme 6 and hereinafter referred to as compounds of the formula I-I. Referring to scheme 6, a compound of the formula I-I may be prepared from the corresponding compound of the formula IVxe2x80x3 where J is oxygen by reacting with a phosphorus sulfide to give an intermediate of the formula XXII. This intermediate is then deprotected as described in scheme I to yield a secondary piperidine of formula VIxe2x80x3 as a free base or a salt of the free base, after which such free base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethy, or a group of the formula K.
The transformation of a compound of formula IVxe2x80x3 to an intermediate of formula XXII is carried out with a phosphorous sulfide such as phosphorous pentasulfide (P2S10) or Lawesson""s reagent [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide] in an non-polar solvent such as benzene, toluene, or xylene. Temperatures may range from 50xc2x0 C. to 160xc2x0 C. Lawesson""s reagent in toluene at 80xc2x0 C. is preferred. Suitable and preferred conditions for the transformation of intermediates of the formula XXII to compounds of the formula I-I are the same ones described in scheme 1 for the preparation of compounds of the formula I-A.
Scheme 7 illustrates the preparation of compounds of the formula I wherein Y is (CH2)m, M is carbon (i.e. xe2x80x94CHxe2x80x94), and R3 is (C1-C6)alkyl. These compounds are designated in scheme 7 and hereinafter referred to as compounds of the formula I-J. Referring to scheme 7, a compound of the formula I-J may be prepared from the corresponding compounds of the formula IVxe2x80x2xe2x80x3 where R3 is hydrogen by deprotonating with a base followed by addition of the appropriate alkylating agent (preferably the appropriate (C1-C6)alkyl chloride, bromide, or iodide) to give an intermediate of formula XXIII. This intermediate is then deprotected as described in scheme 1 to yield a secondary piperidine of formula VIxe2x80x2xe2x80x3 as a free base or a salt of the free base, after which such base or salt is alkylated with a compound of the formula WL, wherein W is defined as above and L is phenyl(C1-C6)alkyl, pyridylmethyl, or a group of the formula K.
Suitable bases for the transformation of a compound of the formula IVxe2x80x2xe2x80x3 to a compound of the formula XXIII include sodium hydride, potassium hydride, lithium diisopropylamide, or n-butyllithium, preferably sodium hydride. The reaction is generally carried out in a polar aprotic solvent such as tetrahydrofuran, dimethylformamide, or 1,2-dimethoxyethane and temperatures may range from xe2x88x9278xc2x0 C. to 80xc2x0 C. The reaction is preferably conducted in dimethylformamide at room temperature. Suitable and preferred conditions for the transformation of intermediates of the formula XXIII to compounds of the formula I-J are the same described in scheme 1 for the preparation of compounds of the formula I-A.
Alternatively, a compound of the formula I-J may be prepared directly from the corresponding compound of the formula I-Axe2x80x2 wherein L is phenyl-(C1-C6)alkyl, pyridylmethyl or a group of the formula K and R3 is hydrogen or I-Bxe2x80x2 wherein L is phenyl or cinnamyl and R3 is hydrogen. Compounds of the formula I-Axe2x80x2 and I-Bxe2x80x2 are prepared according to the methods described in scheme 1 for the preparation of compounds I-A and I-B. Suitable and preferred bases, solvents, and conditions for the transformation of compounds of the formula I-Axe2x80x2 and I-Bxe2x80x2 to compounds of the formula I-J are the same described above for the preparation of compounds of the formula XXIII.
When one or both of R1 and R2 are OH, compounds of the formula I may be prepared from the corresponding xe2x80x94OMe precursor by dealkylation with a Lewis acid such as aluminum trichloride, boron trichloride, boron tribromide, or a protic acid such as aqueous hydrochloric or hydrobromic acid. Suitable solvents for the reaction with Lewis acids include non-polar solvents such as benzene, toluene, dichloromethane, or 1,2-dichlorethane. Temperatures may range from xe2x88x9278xc2x0 C. to 120xc2x0 C. Aqueous hydrobromic acid (48%) at 100-120xc2x0 C. (reflux) is preferred.
When one or both of R1 and R2 are NH2, compounds of the formula I may be prepared from the corresponding NHAc precursor (Ac=acetyl) by acid hydrolysis under the suitable and preferred conditions described above for the formation of starting materials of formula II wherein one or both of R1 and R2 are NH2. The corresponding nitrile (xe2x80x94CN) compounds can be prepared from the corresponding amino compounds via a diazonium salt formation by reacting the amino compound with nitrous acid (made from aqueous hydrochloric acid and sodium nitrite) followed by neutralization and addition to CuCN. Suitable solvents include polar protic solvents such as water or biphasic mixtures with non-polar solvents such as benzene, toluene, or xylene. Neutralization may be carried out by adding a base such as sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide until pH 7. Temperatures may range from xe2x88x9220xc2x0 C. to 60xc2x0 C. It is preferable to carry out the diazonium salt formation in water at 0xc2x0 C., to neutralize with sodium carbonate, and to add the diazonium salt to a biphasic mixture of aqueous CuCN and toluene at 0xc2x0 C., followed by heating to 50xc2x0 C.
When one or both of R1 and R2 are carboxamide (xe2x80x94CONH2), compounds of the formula I may be prepared from the corresponding nitrile (xe2x80x94CN) precursor by reaction with a base such as sodium hydroxide, potassium hydroxide or tetramethylammonium hydroxide in a polar solvent such as water, methanol, ethanol, or t-butanol. Temperatures may range from room temperature to 120xc2x0 C. Potassium hydroxide in t-butanol at 85-100xc2x0 C. is preferred.
Compounds of the formula I other than those of formulae I-A-I-J may be prepared by methods that will be obvious to those skilled in the art from the procedures described above and other known methods.
In each of the above reactions, pressure is not critical. Pressures in the range of about 0.5-3 atm (0.5-3 bars) are suitable, and ambient pressure (generally, about one atmosphere) is preferred as a matter of convenience. Also, for those reactions where the preferred temperature varies with the particular compounds reacted, no preferred temperature is stated. For such reactions, preferred temperatures for particular reactants may be determined by monitoring the reaction using thin layer chromatography.
The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to as the xe2x80x9cactive compounds of the inventionxe2x80x9d) may be administered to a patient by various methods, for example, orally as capsules or tablets, parentally as a sterile solution or suspension, and in some cases, intravenously in the form of a solution. The free base compounds of the invention may be formulated and administered in the form of their pharmaceutically acceptable acid addition salts.
The daily dose of the active compounds of the invention is generally in the range of from about 0.005 to about 300 mg/day, optionally from about 1 to 300 mg/day, and preferably from about 0.01 to about 1 mg/day for the average adult human, and may be administered in single or divided doses.
When incorporated for parenteral administration into a solution or suspension, the active compounds of the invention are present in a concentration of a least 1 weight percent, and preferably between about 4 to 70 weight percent (based on the total weight of the unit). The parenteral dosage unit typically contains between about 5 to 100 mg of active compound(s).
The active compounds of the invention may be administered orally with an inert diluent or an edible carrier, or they may be enclosed in gelatin capsules or compressed into tablets. Such preparations should contain at least 0.5% of active compound(s), but the concentration may vary depending upon the particular form and may be from 4 to 70 weight percent (based on the total weight of the unit). The oral dosage unit typically contains between 1.0 mg to 300 mg of active compound.
The cholinesterase inhibiting activity of the active compounds of the invention may be determined by a number of standard biological or pharmacological tests. One such procedure for determining cholinesterase inhibition is described by Ellman et al. in xe2x80x9cA New and Rapid Colorimetric Determination of Acetylcholinesterase Activityxe2x80x9d, Biochem. Pharm. 1, 88, (1961).